Technical Field
Embodiments of the present invention relate to the use of curcuphenol compounds for increasing expression of major histocompatibility complex class I (MHC-I) antigen in cells, particularly on the surface of diseased cells such as cancer cells, and thereby increasing the immunogenicity of the cells. Also included are related pharmaceutical compositions and methods of use thereof, for instance, to treat various cancers, alone or in combination with other therapies.
Description of the Related Art
Major histocompatibility complex class I (MHC-I) antigens are found on nearly all nucleated cells of the body. The primary function of this class of major histocompatibility complex (MHC) molecules is to display (or present) peptide fragments of intracellular proteins to cytotoxic T lymphocytes (CTLs). Based on this display, CTLs ignore will healthy cells and attack those displaying MHC-bound foreign or otherwise abnormal peptides, including disease-associated peptide (antigens) such as cancer antigens. Thus, the surface expression of MHC-I molecules plays a crucial role in determining the susceptibility of target cells to CTLs.
Many cancerous cells display down-regulated MHC-I cell surface expression (see, for example, Wang et al., JBC. 283: 3951-3959, 2008; Chang et al., Keio J. Med. 52:220-9, 2003; Zagzag et al., Lab Invest. 85:328-41, 2005; and Hewitt, Immunology. 110:163-69, 2003). Reduced MHC-I expression can result at least in part from the down-regulation of multiple factors such as transporters (for example, TAP-1, TAP-2), proteasome components (LMP), and other accessory proteins involved in the antigen presentation and processing pathway. This characteristic may allow cancerous cells to evade immune surveillance and thereby provide a survival advantage against immune activity otherwise designed to eliminate the cells.
Accordingly, there is a need in the art for agents that can increase MHC class I expression in these and other types of diseased cells and thereby improve the ability of the immune system to target such cells for destruction.